US10011651B2ActiveUtilityA1

Methods and compositions for increasing iduronate 2-sulfatase activity in the CNS

84
Assignee: ARMAGEN INCPriority: Oct 9, 2009Filed: Jun 16, 2014Granted: Jul 3, 2018
Est. expiryOct 9, 2029(~3.2 yrs left)· nominal 20-yr term from priority
Inventors:William M. PardridgeRuben J. Boado
A61P 25/28C07K 2319/33A61K 2039/505C07K 2317/92C12N 9/16A61K 38/00C07K 16/18C12Y 301/06013C07K 2319/30C07K 2317/565C07K 16/2869
84
PatentIndex Score
4
Cited by
623
References
32
Claims

Abstract

Provided herein are methods and compositions for treating a subject suffering from a deficiency in iduronate 2-sulfatase in the CNS. The methods include systemic administration of a bifunctional fusion antibody comprising an antibody that crosses the blood brain barrier (BBB) and an iduronate 2-sulfatase.

Claims

exact text as granted — not AI-modified
What is claimed: 
     
       1. A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter's syndrome in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase (IDS) activity, wherein the fusion antibody comprises:
 (a) a fusion protein comprising amino acid sequences of an immunoglobulin heavy chain and an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to a carboxy terminus of the amino acid sequence of the immunoglobulin heavy chain; and 
 (b) an immunoglobulin light chain; 
 
       wherein the fusion antibody crosses a blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin. 
     
     
       2. The method of  claim 1 , wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1). 
     
     
       3. The method of  claim 2 , wherein the fusion antibody comprises formylglycine. 
     
     
       4. The method of  claim 1 , wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
       5. The method of  claim 1 , wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
       6. The method of  claim 1 , wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to a brain, normalized per 50 kg body weight. 
     
     
       7. The method of  claim 1 , wherein the therapeutically effective dose comprises at least about 250,000 units of iduronate-2-sulfatase activity or at least about 25,000 units/Kg of body weight. 
     
     
       8. The method of  claim 1 , wherein the iduronate-2-sulfatase activity of the fusion antibody is at least 10,000 units/mg. 
     
     
       9. The method of  claim 1 , wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of IgG. 
     
     
       10. The method of  claim 1 , wherein the immunoglobulin heavy chain is an immunoglobulin heavy chain of kappa class. 
     
     
       11. The method of  claim 1 , wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG. 
     
     
       12. The method of  claim 1 , wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class. 
     
     
       13. The method of  claim 1 , wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system. 
     
     
       14. The method of  claim 1 , wherein the fusion antibody crosses the BBB via an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor. 
     
     
       15. The method of  claim 1 , wherein the fusion antibody crosses the BBB by binding an insulin receptor. 
     
     
       16. A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter's syndrome in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase activity, wherein the fusion antibody comprises:
 (a) a fusion protein comprising a amino acid sequence that is at least 95% identical to SEQ ID NO:10, and 
 (b) an immunoglobulin light chain; 
 
       wherein the fusion antibody crosses a blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin. 
     
     
       17. The method of  claim 16 , wherein the fusion antibody is post-translationally modified by a sulfatase modifying factor type 1 (SUMF1). 
     
     
       18. The method of  claim 16 , wherein the fusion antibody comprises formylglycine. 
     
     
       19. The method of  claim 16 , wherein at least about 25,000 units of iduronate-2-sulfatase activity are delivered to a brain, normalized per 50 kg body weight. 
     
     
       20. The method of  claim 16 , wherein the therapeutically effective dose comprises at least about 250,000 units of iduronate-2-sulfatase activity or at least about 25,000 units of iduronate-2-sulfatase activity/Kg of body weight. 
     
     
       21. The method of  claim 16 , wherein the iduronate-2-sulfatase activity of the fusion antibody is at least about 10,000 units/mg. 
     
     
       22. The method of  claim 1 , wherein the IDS retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
       23. The method of  claim 16 , wherein the IDS and the immunoglobulin each retains at least 20% of its activity compared to its activity as a separate entity. 
     
     
       24. The method of  claim 16 , wherein the systemic administration is parenteral, intravenous, subcutaneous, intra-muscular, trans-nasal, intra-arterial, transdermal, or respiratory. 
     
     
       25. The method of  claim 16 , wherein the immunoglobulin light chain is an immunoglobulin light chain of IgG. 
     
     
       26. The method of  claim 16 , wherein the immunoglobulin light chain is an immunoglobulin light chain of kappa class. 
     
     
       27. The method of  claim 16 , wherein the fusion antibody crosses the BBB by binding an endogenous BBB receptor-mediated transport system. 
     
     
       28. The method of  claim 16 , wherein the fusion antibody crosses the BBB via an endogenous BBB receptor selected from the group consisting of the insulin receptor, transferrin receptor, leptin receptor, lipoprotein receptor, and the IGF receptor. 
     
     
       29. The method of  claim 16 , wherein the fusion antibody crosses the BBB by binding an insulin receptor. 
     
     
       30. A method for increasing iduronate-2-sulfatase (IDS) activity in a central nervous system of a subject with Hunter's syndrome in need thereof, comprising systemically administering to the subject a therapeutically effective dose of a fusion antibody having iduronate-2-sulfatase activity, wherein the fusion antibody comprises:
 (a) a fusion protein comprising amino acid sequences of an immunoglobulin light chain and an iduronate-2-sulfatase, wherein the amino acid sequence of the iduronate-2-sulfatase is covalently linked to a carboxy terminus of the amino acid sequence of the immunoglobulin light chain; and 
 (b) an immunoglobulin heavy chain; 
 
       wherein the fusion antibody crosses a blood brain barrier (BBB) and catalyzes hydrolysis of 2-sulfate groups of L-iduronate 2-sulfate units of dermatan sulfate, heparan sulfate or heparin. 
     
     
       31. The method of  claim 16 , wherein the fusion antibody crosses the BBB by binding a transferrin receptor. 
     
     
       32. The method of  claim 1 , wherein the fusion antibody crosses the BBB by binding a transferrin receptor.

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